The present invention is concerned with the preparation of compounds, compositions and methods which are useful for treating diseases in human beings which are a result of a body tri-valent ion (i.e. Fe.sup.+++) overload state. Iron overload diseases include thalassemia major, sideroachrestic anemia, Blackfan-Diamond anemia, aplastic anemia, sickle cell anemia, other hemolytic anemias, and a number of other diseases and conditions in which hemosiderosis (a focal or general increase in tissue iron stores without associated tissue damage) occurs. One type of hemosiderosis occurs in most patients after multiple blood transfusions have occurred. Another type of hemosiderosis occurs as the result of the treatment of an anemia found in kidney damaged patients where dialysis is used to remove toxic wastes. Treatment of these conditions has generally involved the administration of a chelating agent having a selective affinity for tissue Fe.sup.+++ ion which can then be excreted as the iron chelate.
The ideal chelating agent for the reduction of tissue iron should have at least the following attributes:
1. Have high selectivity with respect to iron binding; PA1 2. Be essentially metabolically inert; PA1 3. Be essentially non-toxic; PA1 4. Be inexpensive to produce; and PA1 5. Be capable of oral administration. PA1 R.sub.2, R.sub.3, and R.sub.4 are each selected from the group consisting of hydrogen and acyls of the formula: EQU --C(.dbd.O)--R.sub.5 PA1 R.sub.5 is selected from the group consisting of alkyls, substituted alkyls, alkenyls, substituted alkenyls, cycloalkyls, substituted cycloalkyls, arylalkylenes, substituted arylalkylenes, alkylenecycloalkyls, alkylene substituted cycloalkyls, alkynyls, substituted alkynyls, aryls and substituted aryls.
Over the years a number of approaches have been investigated which have some of these attributes. The current drug of choice is deferoxamine, a compound obtained from the microorganism strepotomyces pilosus. Deferoxamine has the following structure: ##STR2##
This material meets the aforementioned criteria except for oral availability. Deferoxamine (as the methanesulfonate salt) has been shown to be most effective when it is delivered parenterally via slow continuous (about an 8-12 hour period) subcutaneous infusion using a portable infusion pump, i.e., a battery powered syringe pump.
This administration route is particularly difficult in view of the widespread occurrance of the disease, thalassemia major, found in the population in countries bordering on the Mediterranean Sea and extending eastward through the Middle East, India to Southeast Asia, and in sickle cell anemia which is prevalent in the populations in Africa.
The present invention concerns certain acyl derivatives of deferoxamine which are effective iron chelators when administered orally.
Some compounds related to the compounds of the present invention are described in the literature by H. Bickel, et al. in Helvitica Chimica Acta, Vol. 46, No. 153, pp 1385-1389, published in 1963 and their related U.S. Patent No. 3,247,197, which are incorporated herein by reference.
The focus of these references are the preparation of N-acyl trihydroxy derivatives of deferoxamine which have the structure: ##STR3## wherein R.sub.1 may be an acyl group. These references mention tetra acyl materials, i.e., materials of the formula: ##STR4## wherein the R groups are each acetyls, as intermediates in the production of their focus compounds. These references do not teach the use of tetra-acyl materials in body iron removal applications nor do they suggest that the tetra-acyl material would be effective when orally administered in these applications.
U.S. Pat. Nos. 3,118,823 and 3,153,621 are concerned with iron chelates of deferoxamine, which are used as growth factors. Additional references of interest in this art include Bickel, et al., Helvitica Chimica Acta, Vol. 43, pp. 2118 ff and 2129 ff, published in 1960; and V. Prelog and Walser, Helvitica Chimica Acta, Vol. 45, pp 631 ff, published in 1962. Finally, D. E. Green and T. B. Okarma briefly reported on studies on the preparation of the tetra-acyl derivatives of deferoxamine and the biological properties of these derivatives. (See Abstracts, 186th Annual American Chemical Society Meeting, Aug. 28-Sept. 2, 1983, Washington, D.C., Abstract No. MEDI 56.